WO 95/18111 addresses fibrinogen receptor antagonists, containing basic and acidic termini, of the formula: ##STR2##
wherein R.sup.1 represents the basic termini, U is an alkylene or heteroatom linker, V may be a heterocycle, and the right hand portion of the molecule represents the acidic termini. The presently claimed compounds do not contain the acidic termini of WO 95/18111.
In U.S. Pat. No. 5,463,071, Himmelsbach et al depict cell aggregation inhibitors which are 5-membered heterocycles of the formula: ##STR3##
wherein the heterocycle may be aromatic and groups A--B--C-- and F--E--D-- are attached to the ring system. A--B--C-- can be a wide variety of substituents including a basic group attached to an aromatic ring. The F--E--D-- group, however, would appear to be an acidic functionality which differs from the present invention. Furthermore, use of these compounds as inhibitors of factor Xa is not discussed.
Baker et al, in U.S. Pat. No. 5,317,103, discuss 5-HT.sub.1 agonists which are indole substituted five-membered heteroaromatic compounds of the formula: ##STR4##
wherein R.sup.1 may be pyrrolidine or piperidine and A may be a basic group including amino and amidino. Baker et al, however, do not indicate that A can be a substituted ring system like that contained in the presently claimed heteroaromatics.
Baker et al, in WO 94/02477, discuss 5-HT.sub.1 agonists which are imidazoles, triazoles, or tetrazoles of the formula: ##STR5##
wherein R.sup.1 represents a nitrogen containing ring system or a nitrogen substituted cyclobutane, and A may be a basic group including amino and amidino. Baker et al, however, do not indicate that A can be a substituted ring system like that contained in the presently claimed heteroaromatics.
Illig et al, in WO 97/47299, illustrate amidino and guanidino heterocycle protease inhibitors of the formula: EQU R.sup.1 --Z--X--Y--W
wherein R.sup.1 can be a substituted aryl group, Z is a two carbon linker containing at least one heteroatome, X is a heterocycle, Y is an optional linker and W is an amidino or guanidino containing group. Compounds of this sort are not considered part of the present invention.
Jackson et al, in WO 97/32583, describe cytokine inhibitors useful for inhibiting angiogenesis. These inhibitors include imidazoles of the formula: ##STR6##
wherein R.sub.1 is a variety of heteroaryl groups, R.sub.4 is phenyl, naphthyl, or a heteroaryl group, and R.sub.2 can be a wide variety of groups. Jackson et al do not teach inhibition of factor Xa. Furthermore, the imidazoles of Jackson et al are not considered part of the present invention.
Activated factor Xa, whose major practical role is the generation of thrombin by the limited proteolysis of prothrombin, holds a central position that links the intrinsic and extrinsic activation mechanisms in the final common pathway of blood coagulation. The generation of thrombin, the final serine protease in the pathway to generate a fibrin clot, from its precursor is amplified by formation of prothrombinase complex (factor Xa, factor V, Ca.sup.2+ and phospholipid). Since it is calculated that one molecule of factor Xa can generate 138 molecules of thrombin (Elodi, S., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa-factor VIII Complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res. 1979, 15, 617-629), inhibition of factor Xa may be more efficient than inactivation of thrombin in interrupting the blood coagulation system.
Therefore, efficacious and specific inhibitors of factor Xa are needed as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. It is thus desirable to discover new factor Xa inhibitors.